Research Group

  • Prof. Michael Mengel, Principal Investigator
  • Dr Konrad Famulski, Co -Investigator
  • Dr Jeff Reeve, Co-Investigator

Location

  • University of Alberta, Edmonton, Canada

Title

  • Integrins in Fibrosis and Atrophy in Human Renal Allografts

Progressive scarring of successfully transplanted kidneys is the limiting factor for long-term organ function after transplantation. Multiple pathologies injure/stress the transplanted kidney and add up over time to the final common phenotype of a scarred transplant which has lost its function. The major function of the kidney transplant is to sustain the equilibrium of body fluids and this is predominately provided by its tubular epithelium. In general, epithelium can recover from injury and stress, but if injury is sustained over time, i.e. adds up, the epithelial cells will de-differentiate and eventually lose their function.

Integrins are basic components of the transmembrane contact between epithelial cells and their adjacent environment, with the ability to transmit intracellular stress to the outside. A subgroup of integrins, the αv-beta integrins, have been shown to activate latent TGF-β, stored in the matrix adjacent to tubular epithelial cells, via this pathway. TGF-β is a crucial cytokine mediating scarring. Preliminary data from the literature and from our own laboratory suggest an important pathogenic connection between epithelial stress/injury, Integrin-expression,TGF-β-activationand scarring.

Therefore, we hypothesize:
1. Injury in renal allografts causes increased epithelial stress which induces expression of TGF-β-activating αv integrins in epithelial cells, leading to increased activation of latent TGF-β, which leads to epithelial de-differentiation and scarring.
2. Interventions against integrins can attenuate epithelial stress, thus abrogate integrin-dependent TGF-β-activation, ameliorate scarring and preserve kidney transplant function.

To prove these hypotheses we plan an analysis of a large repository of human biopsy material from kidney transplants to elucidate and understand, in detail, the integrin-TGF-β-scarring pathway. In addition, we will use mouse models in which the crucial function of integrins at the beginning of this fatal pathogenetic chain towards scarring is abrogated, to test whether interventions against integrins represent a potential therapeutic option in patients with progressive scarring in renal transplants.

Progress Report
Final Report